\r\n\tSQL is worth learning because it’s a programming language that’s in demand in the tech industry and in other sectors that need technology. Most software developers who know SQL earn respectable salaries. Learning SQL can not only enhance your skills, but it can also give you a better understanding of the applications you work with daily. In this book, we will go through the details of SQL and how to use it effectively. The goal of this book is to have many practical application examples that will help learners easily acquire and self-study SQL.
",isbn:"978-1-83969-946-7",printIsbn:"978-1-83969-945-0",pdfIsbn:"978-1-83969-947-4",doi:null,price:0,priceEur:0,priceUsd:0,slug:null,numberOfPages:0,isOpenForSubmission:!0,isSalesforceBook:!1,hash:"d1d908cd61561c1e813552fbd6cb9ed1",bookSignature:"Ph.D. Duc-Man Nguyen and Dr. Van-Loi Nguyen",publishedDate:null,coverURL:"https://cdn.intechopen.com/books/images_new/11919.jpg",keywords:"Database Classification, Types of Databases, SQL Basic, Drop Statement, Aggregate Functions, Conversion Function, Date Function, Mathematical Functions, User-Defined Types, User-Defined Functions, String Data Type, Pivoting Data in SQL",numberOfDownloads:null,numberOfWosCitations:0,numberOfCrossrefCitations:null,numberOfDimensionsCitations:null,numberOfTotalCitations:null,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"May 3rd 2022",dateEndSecondStepPublish:"May 31st 2022",dateEndThirdStepPublish:"July 30th 2022",dateEndFourthStepPublish:"October 18th 2022",dateEndFifthStepPublish:"December 17th 2022",remainingDaysToSecondStep:"12 days",secondStepPassed:!1,currentStepOfPublishingProcess:2,editedByType:null,kuFlag:!1,biosketch:"Dr. Nguyen Duc Man is a member of the DSA-Da Nang Software Association, Vietnam. He was awarded the Award for Excellent effort in Training and Management by the Duy Tan University, Vietnam for several years in a row, and received the Certificate of Merit for Excellent effort in Training and Management by the Ministry of Education and Training, Vietnam. His current research interests are software testing, mobile testing, test automation, test case generation, context-driven testing, and ML for testing.",coeditorOneBiosketch:"Dr. Van-Loi Nguyen received his Master of Engineering in Computer Science from the University of Danang, Vietnam in 2010, and a Ph.D. degree from Soongsil University, Korea, in 2017. He is currently a lecturer at the Vietnam - Korea University of Information and Communication Technology, the University of Danang. He has over 18 years of experience teaching and researching programming, databases, machine learning, information retrieval, multimedia, and artificial intelligence.",coeditorTwoBiosketch:null,coeditorThreeBiosketch:null,coeditorFourBiosketch:null,coeditorFiveBiosketch:null,editors:[{id:"227628",title:"Ph.D.",name:"Duc-Man",middleName:null,surname:"Nguyen",slug:"duc-man-nguyen",fullName:"Duc-Man Nguyen",profilePictureURL:"https://mts.intechopen.com/storage/users/227628/images/system/227628.jpg",biography:'1.\tName:\tNguyen Duc Man\n\tOffice: Room 601, 254 Nguyen Van Linh, Danang, Vietnam\n\tTel: +84-2363 650 403 (Ext 601)\n Mobi: 0904 235 945\n\tEmail: mannd@duytan.edu.vn\n\n2.\tEducation:\nBSc.\tInformation Technology\tDuy Tan University, Vietnam\t1999\nMSc.\tComputer Science\tDanang University, Vietnam\t2009\nPhD.\tComputer Science\tDuy Tan University, Vietnam\t2020\n\n3.\tAcademic experience:\nDuy Tan University, Vietnam\tTeaching\tLecturer\t2004- Present\tFT\n\t\n4.\tNon-academic experience:\nHSD Corporation, Ho Chi Minh, Vietnam\tAnalysis, Design and Code, DB Design\tSoftware Developer\t1999-2001\tFT\nDuy Tan Software Center, Vietnam\tTeam leader, Planning, A&D\tProject Lead\t2001-2003\tFT\n\n5.\tCertifications or professional registrations:\n-\tCertificate for completion of Train the Trainer courses (Software Capstone Project, Requirements Engineering, Software Architecture, Software Project management, software Process and Quality management, Software Integration Practices). Institute of Software Research, Carnegie Mellon University, USA. (2010, 2014, 2016, 2017, 2018, 2019).\n-\t7 Professional Development Hours for participation in the Fundamentals of Program Assessment Workshop, ABET Symposium (2017)\n-\t7 Professional Development Hours for participation in the Self-Study Development Workshop ABET Symposium (2017)\n-\t14 Professional Development Hours for participation at the 2017 ABET\nSymposium, ABET Symposium (2017)\n-\tSoftware Testing and Automation Conference. VISTACON 2011, Ho Chi Minh, Vietnam (2011).\n-\tFagan Software Inspection Method. ECCI Group, Vietnam (2011).\n-\tHP Train the Trainer courses: HP QTP, LoadRunner, Quality Center (2011).\n\n6.\tMembership in professional organizations:\n-\tMember of DSA-Da Nang Software Association, Vietnam.\n\n7.\tHonors and awards:\n-\tAwards for Excellent effort in Training and Management. Duy Tan University, Vietnam (2003, 2006, 2007, 2008, 2009, 2010, 2012).\n-\tCertificate of Merit for Excellent effort in Training and Management. Ministry of Education and Training, Vietnam (2008- 2009, 2010- 2011, 2013- 2014).\n-\tCertificate of Merit of the People Committee of Da Nang. Danang, Vietnam (2011-2012).\n\n8.\tService activities:\n-\tInstitutional service: \n•\tStudents’ Awards Committee \n•\tFaculty Development Committee \n•\tScholarship Committee \n•\tFaculty Council \n\n9.\tPublications and presentations from the past five years:\n\n1.\t\tCheng, Y. H., Chang, P. C., Nguyen, D. M., & Kuo, C. N. (2020). Automatic Music Genre Classification Based on CRNN. Engineering Letters, 29(1).\n2.\t\tHuynh, Q. T., Pham, L. T., Ha, N. H., & Nguyen, D. M. (2020). An Effective Approach for Context Driven Testing in Practice—A Case Study. International Journal of Software Engineering and Knowledge Engineering, 30(09), 1245-1262.\n3.\t\tNguyen, D. M., Huynh, Q. T., Ha, N. H., & Nguyen, T. H. (2020). Automated test input generation via model inference based on user story and acceptance criteria for mobile application development. International Journal of Software Engineering and Knowledge Engineering, 30(03), 399-425.\n4.\t \tNguyen, D. M., Do, H. N., Huynh, Q. T., Vo, D. T., & Ha, N. H. (2018, August). Shinobi: A Novel Approach for Context-Driven Testing (CDT) Using Heuristics and Machine Learning for Web Applications. In International Conference on Industrial Networks and Intelligent Systems (pp. 86-102). Springer, Cham.\n5.\t\tHoang-Nhat, D. O., NGUYEN, D. M., HUYNH, Q. T., & Nhu-Hang, H. A. (2018). One2Explore-Graph Builder for Exploratory Testing from a Novel Approach.\n6.\t\tNguyen, M. D., Huynh, T. Q., & Nguyen, T. H. (2016, November). Improve the Performance of Mobile Applications Based on Code Optimization Techniques Using PMD and Android Lint. In International Symposium on Integrated Uncertainty in Knowledge Modelling and Decision Making (pp. 343-356). Springer, Cham.\n7.\t\tBao Le Nguyen, Nguyen Duc Man, Minh Nguyen Cong and Luong Vo Van (2013). Difficulties in the Operation of an International Program in Vietnam. FICAP-1 Proceedings, BrownWalker Press, 2013, ISBN-13: 9781612337043.\n8.\t\tDuc Nguyen Duc Man, Tien Vu Truong, Nguyen Bao Le (2013). Deployment of Capstone Projects in Software Engineering Education at Duy Tan University as Part of a University-wide Project-based Learning Effort. Learning and Teaching in Computing and Engineering (LaTiCE), IEEE Computer Society -CPS, 2013, E-ISBN :978-0-7695-4960-6 (pp. 184 -191).\n9.\t\tGia Nhu Nguyen, Nhat Tan Tran, Thanh Trung Nguyen and Nguyen Duc Man (2014). The Benefits of CDIO for ABET Preparation from a Hands-on Study in Vietnam. Proceedings of the 10th International CDIO Conference. Barcelona \n10.\t\tVu T Truong, Bao N Le, Man N Duc, Thang M Nguyen (2014). Accessing the Maturity of Teamwork Capabilities through CDIO Projects. Proceedings of the 10th Annual International CDIO Conference. Universitat Politècnica de Catalunya, Barcelona, Spain.\n11.\t\tPhuong A Pham, Man D Nguyen, Long Q Nguyen, Thang M Nguyen, Bao N Le (2014). Learning Computer Programming In Cdio’s Team Settings. Proceedings of the 10th Annual International CDIO Conference. Universitat Politècnica de Catalunya, Barcelona, Spain.\n12.\t\tVo, Q. N., Tran, N. P., Van Dat Ngo, V. H. T., Huynh, Q. T., Ha, N. H., & Nguyen, D. M. LEVERAGE THE BLOCKCHAIN TECHNOLOGY TO MANAGE SMART CONTRACT IN ASSET TRADING. Kỷ yếu Hội nghị KHCN Quốc gia lần thứ XII về Nghiên cứu cơ bản và ứng dụng Công nghệ thông tin (FAIR); Huế, ngày 07-08/6/2019 DOI: 10.15625/vap.2019.00032\n\n13.\t\tHa, N. H., Nguyen, D. M., Liu, C. A., Van Van, T., Nguyen, A. D., & Huynh, Q. T. AN EMPIRICAL STUDY OF THE IMPACT OF THE MPOS SYSTEM ON THE PROCESS CHANGE OF RESTAURANTS. Kỷ yếu Hội nghị KHCN Quốc gia lần thứ XII về Nghiên cứu cơ bản và ứng dụng Công nghệ thông tin (FAIR); Huế, ngày 07-08/6/2019 DOI: 10.15625/vap.2019.00032\n\n14.\t\tNguyễn Thanh Hùng, Nguyễn Đức Mận, Huỳnh Quyết Thắng (2019), Thử Nghiệm Đánh Giá Áp Dụng Một Số Kỹ Thuật Kiểm Thử Để Nâng Cao Độ Tin Cậy Cho Ứng Dụng Di Động Trong Môi Trường Phát Triển Linh Hoạt. Section on Information and Communication Technology (ICT) - No. 13, Journal of Science and Technique - Le Quy Don Technical University - No. 199, ISSN 1859-0209\n15.\t\tHuỳnh Quyết Thắng, Nguyễn Đức Mận, Nguyễn Thị Bảo Trang, Nguyễn Thị Anh Đào (2016). Kỹ thuật kiểm thử hồi qui hiệu quả cho phát triển ứng dụng di động. Kỷ yếu Hội nghị khoa học công nghệ quốc gia lần thứ IX, ngày 4-5/8/2016 - "Nghiên cứu cơ bản và ứng dụng Công nghệ thông tin" (FAIR 2016), trang 255-265. Nhà xuất bản Khoa học tự nhiên và Công nghệ. ISBN 978-604-913-472-2\n\n10.\tRecent professional development activities:\n-\tCoordinator and Assistant Director of ACM/ICPC Asia Regional Contest, Danang, Vietnam (2013). \n-\tParticipated in the 7th National Conference on Fundamental and Applied IT Research (2014).\n-\tAttended the 7 Professional Development Hours the Fundamentals of Program Assessment Workshop (2017).\n-\tParticipated in the 12th National Conference on Fundamental and Applied IT Research (2019).\n-\tINISCOM 2018, INISCOM 2019, KSE 2019, CITA2021, CITA2022\n-\tAttended the CDIO Regional Meeting - Asia-Pacific (2019).',institutionString:"Duy Tan University",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"0",totalChapterViews:"0",totalEditedBooks:"0",institution:{name:"Duy Tan University",institutionURL:null,country:{name:"Vietnam"}}}],coeditorOne:{id:"473326",title:"Dr.",name:"Van-Loi",middleName:null,surname:"Nguyen",slug:"van-loi-nguyen",fullName:"Van-Loi Nguyen",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0033Y00003Sa5QKQAZ/Profile_Picture_2022-05-10T10:01:50.jpg",biography:"Dr. Van-Loi Nguyen received his Master of Engineering in Computer Science from the University of Danang, Vietnam in 2010, and a Ph.D. degree from Soongsil University, Korea in 2017. He is currently a lecturer at the Vietnam - Korea University of Information and Communication Technology, the University of Danang. He has over 18 years of experience teaching and researching in the fields of programming, databases, machine learning, information retrieval, multimedia, and artificial intelligence.",institutionString:"University of Danang",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"0",totalChapterViews:"0",totalEditedBooks:"0",institution:null},coeditorTwo:null,coeditorThree:null,coeditorFour:null,coeditorFive:null,topics:[{id:"9",title:"Computer and Information Science",slug:"computer-and-information-science"}],chapters:null,productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"},personalPublishingAssistant:{id:"429342",firstName:"Zrinka",lastName:"Tomicic",middleName:null,title:"Ms.",imageUrl:"https://mts.intechopen.com/storage/users/429342/images/20008_n.jpg",email:"zrinka@intechopen.com",biography:"As an Author Service Manager, my responsibilities include monitoring and facilitating all publishing activities for authors and editors. 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1. Introduction
Every industry in our world shares the same fundamental motivation - packing as much functionality and power in the smallest possible size. This is naturally effective. In development of an integrated circuits fabrication technology, this trend is projecting in scaling down the minimum circuit element dimensions and circuit power supply voltage. In this way, higher performance and greater mobility is provided for electronic systems during their use. Such an advance, on the other hand, also introduces significantly increased random variations in circuit’s electric specifications. The variations, in return, compromise the reliability already on the top level of electronic systems based on ICs as well as limit the functionality of circuits under constrained energy conditions. Deteriorated reliability of IC fabricated in modern nanotechnologies is significant not only between wafers and its series, but already within single die. Nowadays, ICs fabricated in 7nm or 5nm process nodes can still perform well in digital signal processing. However, their analog counterparts substantially suffer from impaired reliability yet in 130 nm technology. This is of high concern with precise circuits such as operational amplifier (OA), which is usually based on differential topology. Occurrence of any differences in its differential branches, which might be a result of random variations, simultaneously induce degradation of the amplifier key parameters. In terms of circuit electrical parameters, these variations are mirrored by transistor’s threshold voltage (VTH). The VTH variance is commonly characterized by standard deviation in the matched transistor pair with respect to its size as follows:
σΔVTH=AVTHW.L,E1
where AVTH is Pelgrom’s technology coefficient, and W and L is the width and length of the transistor, respectively. The plot in Figure 1 displays ΔVTH for different process nodes according to works [1, 2, 3, 4, 5]. One can observe that downscaled process nodes suffer from much greater variance in VTH with the change of device dimensions. In relative terms, the VTH variance in 45nm process node can reach 16% of mean value according to [6].
Figure 1.
Standard deviation of threshold voltage in matched transistor pair with respect to its size across different process nodes.
The adverse variations can be classified as rather acute - process, voltage and temperature variations, or they can occur after long term use as a consequence of electrical stress. The work [7] thoroughly analyzed the roots of these variations in a transistor as the fundamental IC element.
The following section describes the motivation behind our research. Section 3 explains the design details of the calibration methods implemented in this work. These include digital calibration (DGC) that was experimentally prototyped on a chip, its upgraded and optimized version (DGC2) and Chopper stabilization (CS) technique. Section 4 reveals results of extensive measurements and simulations of the proposed solutions. Finally, the Conclusion summarizes the most important outcomes of the presented research.
2. Motivation
Concluding the discussed state of the art, it is of high importance and it will be increasingly important in the future to compensate for stochastic variations in ICs to maintain reliable circuit operation. The parameter of an OA that is directly tied to any detrimental change in the transistor VTH is the input offset voltage VINOFF. It is therefore, an effective target of any calibration method. Among widely utilized techniques of IC calibration belong fuse trimming (one time or re-programmable), Chopper stabilization and auto-zero (AZ) technique.
In our work, we propose a promising alternative approach based on digital algorithm, that was utilized for the variable gain amplifier. It is fully integrated on-chip system, which is potentially entirely autonomous. This method creates moderate area and energy consumption overhead, but it preserves frequency performance of the calibrated VGA. The methods of calibration substantially differ in fundamentals of operation, which makes the comparison between them difficult. Therefore, we implemented also the CS method for the same VGA. In this way, we can precisely compare the digital calibration to an alternative solution in terms of implementation details.
3. Implementation of calibration methods
This section proposes an insights into design fundamentals of implemented methods of calibration. The fabricated system of DGC, its optimized version for continuous systems and CS will be analyzed. All methods are designed consistently in order to achieve a clear and relevant comparison. They are implemented in standard CMOS 130nm process node and operate under the supply voltage of 600mV. Each method was utilized for the same VGA, which was previously realized in the same technology. The calibration is based on compensation of VINOFF the designed and manufactured VGA exhibits. The VGA is nominally designed to reach DC gain magnitude of 33dB with bandwidth of 17kHz with capacitance load of 10pF.
3.1 Fabricated system of DGC
Figure 2 depicts the block structure of digitally calibrated VGA, which has already been fabricated and evaluated. The calibration subcircuit connects to VGA through sensing (PS1,2) and compensation (PC1,2) ports. These are followed by the control and compensation blocks of the calibration subcircuit.
Figure 2.
Implementation of digital calibration for VGA input offset voltage cancelation.
The control block senses the actual VINOFF through the voltage comparators, as it is tied to output offset voltage with the following formula:
VOUTOFF=ACLG.VINOFF,E2
where VOUTOFF is the output offset voltage and ACLG is amplifier’s closed-loop gain.
The compensation block is connected to VGA topology so it can modify the current flow in its differential branches. As long as VGA outputs (VOP,ON) do not cross the reference voltage (VREF) at comparators’ inputs, the digital-to-analog converter (DAC) adjusts the currents in the VGA. These currents are proportionally projected to VINOFF. When either one of VGA outputs crosses the VREF, the corresponding comparator terminates the clock signal, which drives the compensation block. In this way, VOP and VON are brought close to each other, diminishing the offset voltage.
The direct schematic detail of compensation port is depicted in Figure 3. In this configuration, the DAC output current is mirrored to VGA through the active load of the amplifier, transistors MP1 and MP2. The current mirror is formed by transistors MZ2, MZ3, MZ5 and MZ6. The current mirror on the side of VGA is connected in bulk-driven configuration, which is specific by using the substrate electrodes to control the transistor. The reason for using this topology is better matching in drain-source voltage of mirroring devices MZ5 and MP1 (analogically MZ6 and MP2 for the other VGA branch), as their gate and substrate electrodes are correspondingly tied together. Also the bulk-driven topology performs better in low-voltage conditions of the designed system, as it allows to modify the. This is clear from the following formula:
Figure 3.
The detail of compensation port at schematic level. This represents interface between DGC and VGA.
VTH=VTH0+γ∣2ΦF+VSB∣−∣2ΦF∣,E3
where VSB is the bulk electrode voltage, VTH0 is threshold voltage at VSB=0V, γ is the body effect coefficient and ΦF is the Fermi potential.
The layout of complete DGC system is depicted in Figure 4. The main blocks are highlighted from the principle structure point of view from Figure 2. The dimensions are shown in μm. The VGA covers 18500μm2, while the DGC circuits together take 19000μm2 without the optional trimming fuses.
Figure 4.
The layout of the whole calibration system (dimensions in μm).
Figure 5 displays the micrograph of an experimental chip prototype, where the digital calibration system is marked.
Figure 5.
The micrograph of die with marked area of implemented DGC.
3.2 Optimized system of DGC for continuous operation
As it was described in the previous section, the voltage–current conditions in VGA are modified through the iterations of calibration cycle. The VGA is imbalanced in this process and therefore, cannot perform its intended function. In systems without the need to continuously process the signal, this does not represent an issue, since through proper synchronization the calibration cycle it can be carried out during idle phase. To utilize the digitally calibrated VGA in an application requiring continuous operation, the technique called “Ping-pong” facilitates the necessary continuity [8, 9]. Its principle can be illustrated by the block diagram shown in Figure 6. It uses the calibrated VGA in two identical versions, where the one (VGAX) provides the amplified output while the other (VGAY) is calibrated. When the circuit characteristics change due to temperature or voltage variations, both amplifiers switch their roles. In this way, the output is provided only by already calibrated VGA.
Figure 6.
The “ping-pong” technique for digitally calibrated VGA with continuous output.
Figure 7.
The “ping-pong” technique for digitally calibrated OA with continuous output.
To explain the operation of “Ping-pong” digital calibration (PDGC) more clearly, Figure 7 shows exemplary transient flow of the operation on key signals of system in Figure 6. The temperature change in this example, creates the conditions, in which the calibration is required. During the system initialization, the VGAX is calibrated and its output offset voltage (VOUTOFFX) is suppressed to a range of hysteresis ΔVHYST. The overall system output (VOUT) is consequently switched to VGAX in time t0. When the VINOFFX drifts above ΔVHYST with temperature, the calibration of VGAY begins in time t1. When the calibration cycle is completed, the signal SWY indicates it by a rising edge and the output of VGAY is switched to VOUT in time t2. In this way, the phases of PDGC are autonomously interchanged according to temperature, which is evaluated by a temperature sensor. The maximum overall output offset voltage at VOUT is maintained nearly above ΔVHYST without any substantial corruptions.
During switching VGA versions, the VOUT can suffer from voltage spikes. These produce significantly smaller artifacts of frequency spectrum than spikes resulting from charge injection present in switched calibration methods such as auto-zero technique. Also the spikes can be eliminated by incorporating transfer phase, when the calibrated amplifier is firstly connected as a buffer before being fully switched to the system output [8].
Figure 8.
The improved version of digitally calibrated VGA for integration into “ping-pong” method.
Figure 9.
Optimized control block for digital calibration with upgrades for “ping-pong” approach.
Utilization of “Ping-pong” technique required a few modifications to a system of digitally calibrated VGA in Figure 2. These are incorporated in its upgraded and optimized version, depicted in Figure 8 with more insights into the control logic block shown in Figure 9. In this modified system, the power-on-reset (POR) circuit is present, which is controlled by RPT pin. The POR activates the calibration of idle VGA, when it is required to be switched to the system output. Also the pin SW indicates the calibration cycle is completed. The new version of DGC depicted in Figure 8 also incorporates modifications, which brings better overall efficiency of the discussed method. There is an additional 4-bit DAC, which corrects the residual offset remaining after the main calibration cycle has been completed. In this way, the magnitude of offset voltage is further suppressed. The two sensing comparators of the previous version are now replaced by a single one, which is much simpler solution but with tighter specifications for a successful calibration. A D-type flip-flops in the control block terminate the distribution of CLK signal when the calibration is finished, which prevents unintended launch of another calibration cycle.
The optimized DGC from Figure 8 covers only 6000μm2 instead of 19000μm2 taken by the original version. Also the power consumption of calibration circuits is lowered from 41μW to just 6μW, which is almost 7 times lower.
3.3 Chopper stabilization
In order to obtain precise comparison of calibration methods, so-called chopper stabilization has been utilized for the same VGA as in DGC, serving as an alternative method. In this way, the figure of merit (FOM) can be defined by considering the chip area coverage, power consumption and residual VINOFF, as main parameters obtained over sufficient number of samples. The proposed chopper stabilization has been build according to the basic principle, without complex techniques, which would require an auxiliary amplifiers.
Figure 10.
The block diagram of chopper-stabilized VGA.
The block diagram of chopper-stabilized VGA is shown in Figure 10. It consists of modulator and demodulator employed at the VGA input and output, respectively. These are switched by signal mt with frequency of 20kHz so that it falls in VGA bandwidth. In order to make the comparison to DGC objective and relevant, we established the limit for total harmonic distortion (THD) at the value of 1%. The output of demodulator provides the carrier signal mt with the envelope formed by VIN. Therefore, the low-pass filter needs to be employed at each output channel. As there are requirements for low THD and low corner frequency (fc) of 10kHz (suppressing mt), the filter must incorporate significantly large values of capacitor and resistor. Moreover, the fc needs to be as close as possible to mt frequency, so that the filter cuts the smaller portion of overall VGA bandwidth. To meet this requirement, the filter needs to reach significant steepness or in other words, the order. The mentioned specifications demand rather complex solution consisting of a frequency filter with large values of passive components. It was realized as Sallen-Key active filter of 2nd order, which is used 3 times in series for each VGA output channel. These two pairs of the filter cover together approximately 800 000 μm2. While the VGA occupies only 18 500 μm2, using the CS in this conditions would create a tremendous area overhead.
The large silicon area covered by frequency filters can be mitigated by switched capacitors that are used instead of classic resistors. On the other hand, the switching frequency in this case, would demand yet another design solution to maintain a low distortion of the processed input signal.
4. Verification
Fabricated system of DGC, described in section 3.1 was experimentally verified. The measurements have been carried out on 10 packaged IC samples at the ambient temperature of 27°C. All implemented methods of calibration for VGA were extensively verified through simulations in Cadence environment. These included process corner analysis, Monte Carlo (MC) and RelXpert reliability analysis. Each simulation type has been carried out in the temperature range from −20°C to 85°C. MC was performed with 150 sample scenarios. Reliability analysis simulates the operation of an IC after initial electrical stress and operation after 10 years of stress. It is based on the bias temperature instability (BTI) and hot carrier injection (HCI), the phenomena which gradually degrade the IC reliability and dependability. It does not consider time dependent dielectric breakdown since this is rather acute in nature. Reliability analysis considered simultaneously the process corners and geometry mismatch as well.
In order to optimally design the calibration circuits, the experimental measurements of VINOFF in the same VGA without calibration (previously fabricated) hardware were performed. Measurements were carried out on 60 naked dies. The resulting offset distribution is displayed in Figure 11 and compared to MC result distribution. 3σ range of VINOFF reaches approximately 10mV. Hypothetically, with the VGA nominal gain of 33 dB such VINOFF would project to 460mV in the differential output voltage. Considering the VGA being supplied by 600mV, its outputs would reach almost to the supply rails range even in the optimum operating point.
Figure 11.
Distribution of VINOFF of uncalibrated VGA. Comparison of experimental measurements and MC analysis.
Histograms depicted in Figures 12–14 compare the MC simulation results of VINOFF of digitally calibrated VGA, chopper-stabilized VGA and VGA without a calibration. The achieved results prove a comparable performance of DGC and CS in terms of standard deviation, while CS reaches better centering of distributions towards 0V. Both methods of calibration successfully suppress the VINOFF in magnitude of orders through the whole temperature range.
Figure 12.
MC simulation results of VINOFF in digitally calibrated VGA, chopper stabilized VGA and VGA without calibration. Temperature of −20C.
Figure 13.
MC simulation results of VINOFF in digitally calibrated VGA, chopper stabilized VGA and VGA without calibration. Temperature of 27°C.
Figure 14.
MC simulation results of VINOFF in digitally calibrated VGA, Chopper stabilized VGA and VGA without calibration. Temperature of 85°C.
Figure 15 displays the transient flow of digital calibration cycle through the VGA output voltages. It compares the best and worst case scenarios of technology process corners after the initial stress and after 10 years of operation. After the calibration is successfully completed, the VGA is fed the harmonic signal of 0.5mV differential amplitude and frequency of 1kHz. The detail of plot in right-hand side part of Figure 15 zooms the differential output voltage of the calibrated VGA in proper operation. The calibration cycle was controlled by clock signal with frequency of 1kHz. Figure 16 displays the measured flow of calibration cycle also through VGA output voltages. The best and worst cases of the measurement and simulation results are compared. The calibration was performed with CLK frequency of 350kHz. The whole cycle from beginning to the point where VGA is ready for proper operation lasts between 210μs and 319μs. Figure 17 compares the gain of VGA obtained by measurement and simulation in the best and worst cases. Measurements were carried out using the maximum input signal amplitude for VGA, which allowed to keep the total harmonic distortion under 1%. As one can observe, the experimental results fit the simulations very well. The upgraded, more precise DGC version, described in section 3.2 is actually being re-designed at the moment. Figures 18–20 compares the MC simulation results of VINOFF to the prototype version over the industrial temperature range. The mean value of offset is compensated in one order of magnitude further towards 0V by means of new DGC. Standard deviation remains approximately constant. The reason behind it is supposed to be the offset voltage of sensing comparator in DGC. It causes premature termination of main calibration cycle, which alone produces excessive residual VINOFF. Consequently, the issue is amplified because faulty termination launches correction calibration cycle in the wrong direction, enhancing the residual VINOFF even further. On the other hand, this shortcoming of upgraded DGC can be easily resolved by auto-zeroing the sensing comparator. As it processes discontinuous signal (proportional to DAC output), the proper synchronization of switching the AZ sample phase with CLK of calibration would preserve the overall DGC progress untouched.
Figure 15.
Reliability analysis of digitally calibrated VGA considering process corners and geometry mismatch. The calibration cycle at fresh IC is compared to the IC of 10 years of age.
Figure 16.
Transient flow of the calibration cycle. The comparison of the best and the worst case of measurement and simulation.
Figure 17.
Measured vs. simulated gain of the digitally calibrated VGA.
Figure 18.
Measured vs. simulated gain of the digitally calibrated VGA for temperature of −20°C.
Figure 19.
Measured vs. simulated gain of the digitally calibrated VGA for temperature of 27°C.
Figure 20.
Measured vs. simulated gain of the digitally calibrated VGA for temperature of 85°C.
Table 1 summarizes the most important results of calibration methods, implemented in this work. There are compared measurement and simulation results of prototype DGC version and simulation results of upgraded DGC (DGC2) and CS. The whole data were obtained at room temperature of 27°C for the purpose of comparison to related works shown in Table 2. As all details in these designs were accessible, the figure of merit (FOM) has been determined according to the following formula:
DGC
DGC23)
CS
min
max
μ
σ
μ
σ
μ
σ
Year
2020
Node
nm
130
VDD
V
0.6
SOA1)
.103μm2
18.4
SCH2)
.103μm2
19
6
800
POA1)
μW
—
—
38
3
38.5
3.6
30.4
3.1
PCH2)
μW
—
—
41
6.1
5.6
0.7
62.7
11
VINOFF
μV
13
167
22
206
18.5
390
2.75
95
THD
%
1
0.04
0.02
0.83
0.07
0.05
0.03
ADC
dB
31
33
35.3
2.7
33.6
8.2
30.23
2.2
BW
kHz
12.6
13.5
15.25
2.2
15.9
2
0.9
—
GBW
MHz
0.6
0.75
0.06
800
61
3
—
FOM
−
—
41
340
4
Results
Meas.
Sim.
Calibration
Dig.
Chop.
Table 1.
The main results of the proposed calibrated systems.
Chip area coverage (S) and power consumption (P) of the calibrated OA.
Chip area coverage (S) and power consumption (P) of the calibration hardware.
Upgraded and optimized version of the prototyped DGC.
Bold values are emphasize the parameter FOM, which is one of most important results in this work.
The results comparison of the proposed work to related works.
Chip area coverage (S) and power consumption (P) of the calibrated OA.
Chip area coverage (S) and power consumption (P) of calibration hardware.
These works does not contain information about THD, therefore the comparison is not fully relevant.Bold values are emphasize the parameter FOM, which is one of most important results in this work.
FOM=1000μVINOFF.A.PE4
where the parameters are:
μVINOFF - mean value of residual input offset voltage after calibration over sufficient number of samples,
A=ACH/ACC - ratio of calibration hardware die area versus area of calibrated circuit,
P=PCH/PCC - power consumption of calibration hardware versus power consumption of the calibrated circuit.
The FOM value evaluates the power and area efficiency of the obtained calibration result over a sufficient number of samples. Its coefficients are in denominator, and therefore, the greater value of FOM proves better overall performance of calibration method. The value of coefficients is multiplied by 1000 in numerator to shift the results into the order of tens to thousands. The crucial condition for objectivity in this comparison is the THD of the amplifier is maintained under 1% at any method of calibration.
It is obvious that CS outperforms even DGC2 in term of VINOFF. It maintains the nominally designed low-frequency gain (ADC) at 30.23dB. On the other hand, the bandwidth (BW) is seriously constrained due to extensive filtering and the principle of CS alone.
However, this is not an issue with DGC and DGC2 approach, as the simulation results of BW after the calibration converge on the nominally designed 17kHz. The measurement value of BW exhibits a certain decline, which could be assigned to parasitic capacitances associated with measurement setup, as well as to the measurement error due to small signal amplitude. Thanks to optimization of occupied silicon area and power consumption the DGC2 outperforms CS according to FOM. Table 2 compares the proposed results to related works in the scientific area. This comparison was problematic as the calibration methods are most often built in more complex systems as DBS receiver circuit [10] and others. They are therefore side topics and authors do not mention the details, which are critical in terms of calibration. One such limitation is missing the level of THD, which sets equal conditions with calibration methods, presented in this chapter. The FOM values proves DGC2 for being a competitive solution for calibration of analog integrated circuits.
Figure 21 depicts the setup for automated measurements, which served for the evaluation of prototype chips.
Figure 21.
The automated measurement setup for evaluation of the prototype calibrated systems.
5. Conclusions
Prevalent trends in IC fabrication reveal an increasing sensitivity to process, voltage, temperature variations and aging that projects directly into degradation of the overall perfomance of integrated systems. While digital systems are proven to be robust enough to above mentioned fluctuations even below 10nm process node, their analog counterparts suffer from significantly decreased yield already in 130nm technology node. This is confirmed by an actual research and also by experimental results provided within this chapter. Various methods of calibration have been presented and proven to effectively aid analog integrated circuits in preserving their reliability. These methods are rather complex, which constricts them for very specific use. This chapter extensively analyses the digitally controlled calibration method aimed at compensating the input offset voltage of the variable-gain amplifier. Chopper stabilization technique was implemented for the same amplifier, ensuring an objective comparison. Digital calibration was verified by simulations and experimental measurements on a prototype chip, which uniformly proved the reliable performance of the calibrated system. The established figure of merit shows that digital calibration represents an effective solution for preservation of reliability level in continuous systems with low distortion. The proposed method operates with lowest supply voltage level and also achieves the lowest silicon area and power consumption between the compared solutions, while maintaining competitive level of the calibrated input offset voltage. The area, which is added by calibration hardware can be mitigated by relieving demands for robustness of the calibrated circuit. By means of digital processing the method itself is robust against electrical variations.
Concluding the provided results, the digital calibration proves to be a promising solution in aiding the analog ultra-low voltage systems on chip towards a reliable operation, which is enormous challenge in modern nanoscale technologies. The proposed method is area and power efficient, while its operation remains stable over at least 10 years life span. It can be easily integrated along the calibrated circuit on a single chip in deep sub-micron process nodes. Taking into account the further research, it can become fully autonomous. In this way, the handling of calibrated circuit remains intact of calibration management.
Acknowledgments
This research was supported in part by the Slovak Research and Development Agency under grant APVV-19-0392, and ECSEL JU under project PROGRESSUS (Agr. No. 876868).
\n',keywords:"on-chip digital calibration, PVT variations, aging compensation, reliability, input offset voltage, continuous operation, ultra-low voltage",chapterPDFUrl:"https://cdn.intechopen.com/pdfs/75609.pdf",chapterXML:"https://mts.intechopen.com/source/xml/75609.xml",downloadPdfUrl:"/chapter/pdf-download/75609",previewPdfUrl:"/chapter/pdf-preview/75609",totalDownloads:292,totalViews:0,totalCrossrefCites:0,totalDimensionsCites:0,totalAltmetricsMentions:0,impactScore:0,impactScorePercentile:43,impactScoreQuartile:2,hasAltmetrics:0,dateSubmitted:"August 5th 2020",dateReviewed:"February 13th 2021",datePrePublished:"March 9th 2021",datePublished:"June 16th 2021",dateFinished:"March 9th 2021",readingETA:"0",abstract:"This chapter deals with digital method of calibration for analog integrated circuits as a means of extending its lifetime and reliability, which consequently affects the reliability the analog electronic system as a whole. The proposed method can compensate for drift in circuit’s electrical parameters, which occurs either in a long term due to aging and electrical stress or it is rather more acute, being caused by process, voltage and temperature variations. The chapter reveals the implementation of ultra-low voltage on-chip system of digitally calibrated variable-gain amplifier (VGA), fabricated in CMOS 130 nm technology. It operates reliably under supply voltage of 600mV with 10% variation, in temperature range from −20°C to 85°C. Simulations suggest that the system will preserve its parameters for at least 10 years of operation. Experimental verification over 10 packaged integrated circuit (IC) samples shows the input offset voltage of VGA is suppressed in range of 13μV to 167μV. With calibration the VGA closely meets its nominally designed essential specifications as voltage gain or bandwidth. Digital calibration is comprehensively compared to its widely used alternative, Chopper stabilization through its implementation for the same VGA.",reviewType:"peer-reviewed",bibtexUrl:"/chapter/bibtex/75609",risUrl:"/chapter/ris/75609",book:{id:"10384",slug:"practical-applications-in-reliability-engineering"},signatures:"Michal Sovcik, Lukas Nagy, Viera Stopjakova and Daniel Arbet",authors:[{id:"317026",title:"Dr.",name:"Daniel",middleName:null,surname:"Arbet",fullName:"Daniel Arbet",slug:"daniel-arbet",email:"daniel.arbet@stuba.sk",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",institution:null},{id:"317089",title:"Prof.",name:"Viera",middleName:null,surname:"Stopjakova",fullName:"Viera Stopjakova",slug:"viera-stopjakova",email:"viera.stopjakova@stuba.sk",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",institution:null},{id:"317114",title:"Dr.",name:"Lukas",middleName:null,surname:"Nagy",fullName:"Lukas Nagy",slug:"lukas-nagy",email:"lukas.nagy@stuba.sk",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",institution:{name:"Slovak University of Technology in Bratislava",institutionURL:null,country:{name:"Slovakia"}}},{id:"328726",title:"MSc.",name:"Michal",middleName:null,surname:"Sovcik",fullName:"Michal Sovcik",slug:"michal-sovcik",email:"michal.sovcik@stuba.sk",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",institution:{name:"Slovak University of Technology in Bratislava",institutionURL:null,country:{name:"Slovakia"}}}],sections:[{id:"sec_1",title:"1. Introduction",level:"1"},{id:"sec_2",title:"2. Motivation",level:"1"},{id:"sec_3",title:"3. Implementation of calibration methods",level:"1"},{id:"sec_3_2",title:"3.1 Fabricated system of DGC",level:"2"},{id:"sec_4_2",title:"3.2 Optimized system of DGC for continuous operation",level:"2"},{id:"sec_5_2",title:"3.3 Chopper stabilization",level:"2"},{id:"sec_7",title:"4. Verification",level:"1"},{id:"sec_8",title:"5. Conclusions",level:"1"},{id:"sec_9",title:"Acknowledgments",level:"1"}],chapterReferences:[{id:"B1",body:'Z. Al Tarawneh, The effects of process variations on performance and robustness of bulk CMOS and SOI implementations of C-elements. PhD thesis, Newcastle University, 2011'},{id:"B2",body:'B. C. P. et al, ““variability evaluation of 28nm fd-soi technology at cryogenic temperatures down to 100mk for quantum computing,” in Technical Highlights from the 2020 Symposia on VLSI Technology and Circuits [to be published], 2020'},{id:"B3",body:'G. Angelov, D. Nikolov, M. Spasova, and R. Rusev, “Study of process variability-sensitive local device parameters for 14-nm bulk finfets,” in 2020 43rd International Spring Seminar on Electronics Technology (ISSE), pp. 1–4, 2020'},{id:"B4",body:'F. A. et al., “Low leakage and low variability ultra-thin body and buried oxide (ut2b) soi technology for 20nm low power cmos and beyond,” in 2010 Symposium on VLSI Technology, pp. 57–58, 2010'},{id:"B5",body:'H. Edwards, T. Chatterjee, M. Kassem, G. Gomez, F.-C. Hou, and X. Wu, “Device physics origin and solutions to threshold voltage fluctuations in sub 130 nm cmos incorporating halo implant,” 10 2010'},{id:"B6",body:'M. Onabajo and J. Silva-Martinez, Analog circuit design for process variation-resilient systems-on-a-chip. Springer Science & Business Media, 2012'},{id:"B7",body:'D. Wolpert and P. Ampadu, Managing Temperature Effects in Nanoscale Adaptive Systems. Springer New York, 2011'},{id:"B8",body:'M. Pastre and M. Kayal, Methodology for the digital calibration of analog circuits and systems. Springer, 2006'},{id:"B9",body:'M. Kayal, R. T. L. Saez, and M. Declercq, “An automatic offset compensation technique applicable to existing operational amplifier core cell,” in Proceedings of the IEEE 1998 Custom Integrated Circuits Conference (Cat. No.98CH36143), pp. 419–422, May 1998'},{id:"B10",body:'S. Li, J. Li, X. Gu, H. Wang, M. Tang, and Z. Zhuang, “A continuously and widely tunable 5 db-nf 89.5 db-gain 85.5 db-dr cmos tv receiver with digitally-assisted calibration for multi-standard dbs applications,” IEEE Journal of Solid-State Circuits, vol. 48, pp. 2762–2774, Nov 2013'},{id:"B11",body:'Y. Zhang, Y. Fei, Z. Peng, and F. Huang, “A 250mhz 60db gain control range 1db gain step programmable gain amplifier with dc-offset calibration,” in 2015 International Symposium on Intelligent Signal Processing and Communication Systems (ISPACS), pp. 227–230, Nov 2015'},{id:"B12",body:'P. Mak, S. U, and R. P. Martins, “On the design of a programmable-gain amplifier with built-in compact dc-offset cancellers for very low-voltage wlan systems,” IEEE Transactions on Circuits and Systems I: Regular Papers, vol. 55, pp. 496–509, March 2008'},{id:"B13",body:'Z. Cheng and J. Bor, “A cmos variable gain amplifier with dc offset calibration loop for wireless communications,” in 2006 International Symposium on VLSI Design, Automation and Test, pp. 1–4, 2006'},{id:"B14",body:'Xiaojie Chu, Min Lin, Zheng Gong, Yin Shi, and Fa Foster Dai, “A cmos programmable gain amplifier with a novel dc-offset cancellation technique,” in IEEE Custom Integrated Circuits Conference 2010, pp. 1–4, 2010'}],footnotes:[],contributors:[{corresp:null,contributorFullName:"Michal Sovcik",address:null,affiliation:'
Slovak University of Technology, Bratislava, Slovakia
Slovak University of Technology, Bratislava, Slovakia
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Bernstein",authors:[{id:"203723",title:"Prof.",name:"Joseph",middleName:null,surname:"Bernstein",fullName:"Joseph Bernstein",slug:"joseph-bernstein"}]},{id:"55975",title:"The Importance of Interconnection Technologies’ Reliability of Power Electronic Packages",slug:"the-importance-of-interconnection-technologies-reliability-of-power-electronic-packages",signatures:"Sébastien Jacques",authors:[{id:"202576",title:"Dr.",name:"Sébastien",middleName:null,surname:"Jacques",fullName:"Sébastien Jacques",slug:"sebastien-jacques"}]},{id:"58020",title:"Reliability Prediction of Smart Maximum Power Point Converter for PV Applications",slug:"reliability-prediction-of-smart-maximum-power-point-converter-for-pv-applications",signatures:"Giovanna Adinolfi and Giorgio Graditi",authors:[{id:"219917",title:"Dr.",name:"Giorgio",middleName:null,surname:"Graditi",fullName:"Giorgio Graditi",slug:"giorgio-graditi"},{id:"219918",title:"Dr.",name:"Giovanna",middleName:null,surname:"Adinolfi",fullName:"Giovanna Adinolfi",slug:"giovanna-adinolfi"}]},{id:"55702",title:"Low‐Frequency Noise and Resistance as Reliability Indicators of Mechanically and Electrically Strained Thick‐Film Resistors",slug:"low-frequency-noise-and-resistance-as-reliability-indicators-of-mechanically-and-electrically-strain",signatures:"Zdravko Stanimirović",authors:[{id:"3420",title:"Dr.",name:"Ivanka",middleName:null,surname:"Stanimirović",fullName:"Ivanka Stanimirović",slug:"ivanka-stanimirovic"},{id:"3421",title:"Dr.",name:"Zdravko",middleName:null,surname:"Stanimirović",fullName:"Zdravko Stanimirović",slug:"zdravko-stanimirovic"}]},{id:"55915",title:"Coordination and Selectivity of Protection Devices with Reliability Assessment in Distribution Systems",slug:"coordination-and-selectivity-of-protection-devices-with-reliability-assessment-in-distribution-syste",signatures:"Marco Antônio Ferreira Boaski, Caio dos Santos, Mauricio\nSperandio, Daniel Pinheiro Bernardon, Maicon Jaderson Ramos and\nDaniel Sperb Porto",authors:[{id:"180154",title:"Dr.",name:"Daniel",middleName:"P",surname:"Bernardon",fullName:"Daniel Bernardon",slug:"daniel-bernardon"},{id:"203811",title:"BSc.",name:"Marco",middleName:null,surname:"Boaski",fullName:"Marco Boaski",slug:"marco-boaski"},{id:"203812",title:"Dr.",name:"Mauricio",middleName:null,surname:"Sperandio",fullName:"Mauricio Sperandio",slug:"mauricio-sperandio"},{id:"203813",title:"Mr.",name:"Caio",middleName:null,surname:"Santos",fullName:"Caio Santos",slug:"caio-santos"},{id:"203814",title:"MSc.",name:"Maicon",middleName:null,surname:"Ramos",fullName:"Maicon Ramos",slug:"maicon-ramos"},{id:"203833",title:"MSc.",name:"Daniel",middleName:null,surname:"Porto",fullName:"Daniel Porto",slug:"daniel-porto"}]},{id:"57453",title:"An Analysis of Software and Hardware Development in the PMU-Based Technology and Suggestions Regarding Its Implementation in the Polish Power Grid",slug:"an-analysis-of-software-and-hardware-development-in-the-pmu-based-technology-and-suggestions-regardi",signatures:"Michał Szewczyk",authors:[{id:"22653",title:"Dr.",name:"Michał",middleName:null,surname:"Szewczyk",fullName:"Michał Szewczyk",slug:"michal-szewczyk"}]},{id:"57936",title:"Power System Reliability: Mathematical Models and Applications",slug:"power-system-reliability-mathematical-models-and-applications",signatures:"Rabah Medjoudj, Hassiba Bediaf and Djamil Aissani",authors:[{id:"182165",title:"Dr.",name:"Rabah",middleName:null,surname:"Medjoudj",fullName:"Rabah Medjoudj",slug:"rabah-medjoudj"},{id:"182167",title:"Prof.",name:"Djamil",middleName:null,surname:"Aissani",fullName:"Djamil Aissani",slug:"djamil-aissani"},{id:"208149",title:"Ms.",name:"Hassiba",middleName:null,surname:"Bediaf",fullName:"Hassiba Bediaf",slug:"hassiba-bediaf"}]},{id:"56098",title:"Techno-Economic Feasibility Study of Autonomous Hybrid AC/DC Microgrid System",slug:"techno-economic-feasibility-study-of-autonomous-hybrid-ac-dc-microgrid-system",signatures:"Atanda K. 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1. Introduction
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Vitamin D is a secosteroid hormone, which is known to be related to the regulation of the musculoskeletal system. It affects calcium and phosphate metabolism and is related to bone health. Recently, the extraskeletal effects of vitamin D are under intense research and have attracted the interest of the scientific community [1, 2, 3, 4, 5, 6]. In particular, the relationship of vitamin D with the immune system is in the focus of scientific evaluation [7, 8, 9]. In the chapter herein, the effects of vitamin D on the immune system will be discussed, and the relationship of vitamin D deficiency with the development of autoimmune diseases will be reviewed.
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2. Vitamin D and the immune system
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The classic function of vitamin D is to enhance intestinal absorption of calcium by regulating several calcium transport proteins in the small intestine [4]. However, various cells express the vitamin D receptor (VDR) and the vitamin D activating enzyme 1-α-hydroxylase. Various cells of the immune system also express the VDR and harbor 1-α-hydroxylase [10, 11]. Thus, cells of the immune system respond to vitamin D and also activate vitamin D in a paracrine or autocrine fashion. The extra-renal 1-α-hydroxylase is not upregulated by PTH, and thus, production of 1,25(OH)2D3 is dependent on concentrations of the substrate 25(OH)D3, and it may be regulated by inflammatory signals, such as lipopolysaccharide and cytokines [12, 13]. Cells of the immune system, which express the VDR and harbor 1-α-hydroxylase, are macrophages, T cells, dendritic cells, monocytes, and B cells (Figure 1) [9]. Vitamin D is involved in the regulation of the innate immunity as it enhances the defense system of the organism against microbes and other pathogenic organisms, and it modulates the adaptive immune system through direct effects on T-cell activation and on the phenotype and function of antigen-presenting cells, particularly dendritic cells.
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Figure 1.
Cells of the immune system regulated in part by vitamin D.
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2.1 Vitamin D and the innate immune system
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The innate immune system is a first line of defense against infection. Vitamin D is a regulator of the innate immune system [1, 14]. The first data on the effect of vitamin D on the innate immune system have been generated on the treatment of diseases caused by mycobacteria, such as tuberculosis and leprosy [15, 16, 17, 18]. Vitamin D has been used as a treatment of infections for more than 150 years. In 1849, Williams reported favorable results with the use of cod-liver-oil, an excellent source of vitamin D, in the treatment of patients with tuberculosis [19]. Fifty years later, Niels Finsen received the third Nobel Prize in Medicine for his description of using UV light, an effective method to increase vitamin D status, to treat lupus vulgaris, a cutaneous form of tuberculosis [20, 21]. Alfred Windaus contributed to the discovery of the chemical structure of vitamin D2 and vitamin D3 found in cod-liver-oil and received the Nobel prize [22, 23, 24]. Thereafter, several groups used vitamin D2 and D3 as a treatment for tuberculosis [22, 25]. Rook et al. [26] demonstrated in the 1980s that 1,25(OH)2D3 inhibited the proliferation of Mycobacterium tuberculosis in culture. Vitamin D enhances the production of defensin β2 and cathelicidin in response to infection by macrophages, monocytes, and keratinocytes [12]. Humans have only one cathelicidin, which is cleaved to form LL-37 [27]. Cells of the immune system including neutrophils and macrophages and cells lining epithelial surfaces that are constantly exposed to potential pathogens such as the skin, the respiratory, and the gastrointestinal tract produce cathelicidin [28, 29, 30]. Cathelicidin has broad antimicrobial activity against Gram-positive and Gram-negative bacteria, as well as certain viruses and fungi [31]. The killing mechanism of cathelicidin involves bacterial lysis by destabilizing cell membrane [32]. Treatment with 1,25(OH)2D3 upregulates cathelicidin mRNA in several cell lines. Thus, it appears that 1,25(OH)2D3 upregulates antimicrobial peptide production, primarily cathelicidin, on a variety of different cells [33]. Studies indicate that 25(OH)D3, the major circulating form of vitamin D to determine vitamin D status, is important for local production of 1,25(OH)2D3 to upregulate cathelicidin production in the skin and macrophages. Exposing human monocytes to pathogens increases the expression of both 1,25(OH)2D3 and VDR, thus increasing both the local production of 1,25(OH)2D3 and the ability of the cell to respond to it [12]. Since keratinocytes also possess 25-α-hydroxylase, UV light may directly stimulate cathelicidin production by providing the substrate 25(OH)D3 directly from vitamin D3 produced within the skin [34, 35]. Macrophages also respond to vitamin D increasing their antimicrobial activity, however, heterogeneously [36, 37]. Macrophages formed after interleukin-15 stimulus respond to vitamin D increasing their antimicrobial activity, whereas macrophages formed after stimulation by interleukin-10 respond to vitamin D stimulus weakly.
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Data regarding other infections also exist. Thus, children with low vitamin D status may be more prone to urinary tract infections due to low production of cathelicidin and defensin β2 [38, 39]. Also, adults with asthma may be less prone to infection after treatment with vitamin D due to increased production of cathelidicin and modulation of inflammatory cytokines [40, 41]. Low levels of vitamin D may be related to chronic obstructive pulmonary disease severity [42]. Vitamin D may increase resistance to HIV infection. Low levels of vitamin D have been associated with disease progression and mortality [43]. The ability of the immune cells to hydroxylate 25(OH)D3 locally suggests that in patients with infections, it may be better to administer 25(OH)D3 rather than hydroxylated metabolites to allow for local production and the feedback system to function.
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2.2 Vitamin D and autoimmunity
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The natural history of autoimmunity remains largely unknown. However, the theory is that both genetic susceptibility and environmental factors play a role in the development of clinical autoimmune disease. Vitamin D has known immunomodulatory effects on a wide range of immune cells, including T and dendritic cells [44, 45]. Each of these immune cells expresses VDR and produces the enzymes 1-α-hydroxylase and 24-hydroxylase and is therefore capable of locally producing active 1,25(OH)2D3 [46, 47, 48, 49]. Activation of CD4+ T cells results in a significant increase in VDR expression enabling regulation of many genes responsive to 1,25(OH)2D3 [50]. 1,25(OH)2D3 suppresses T-cell receptor induced T cell proliferation and changes their cytokine expression. The overall shift is away from T helper Th1 phenotype toward a more tolerogenic Th2 response [51, 52, 53]. Vitamin D appears to directly inhibit Th1 cells and may additionally modulate a skewing toward a Th2 response [54]. Th17 cells are a subset of CD4+ T cells involved in organ-specific autoimmunity playing a role in maintaining inflammation, which can lead to tissue damage. 1,25(OH)2D3 suppresses autoimmunity and tissue destruction by inhibiting the Th17 response at several levels [55, 56]. Altogether, the evidence suggests an important role for vitamin D in influencing T-cell responses and in tempering inflammation and tissue damage.
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Vitamin D appears to have a direct effect on B cells and inhibits immunoglobulin production [57]. Additionally, differentiation of B cells is interrupted when exposed to 1,25(OH)2D3. 1,25(OH)2D3 also has effects on dendritic cells. Dendritic cells have important functions in maintaining both protective immunity and self-tolerance [58, 59]. Physiologic levels of 1,25(OH)2D3 inhibit maturation of dendritic cells and maintain an immature and tolerogenic phenotype with inhibition of activation markers such as MHC class II, CD40, and others and upregulation of inhibitory molecules [60, 61]. Thus, it appears that the maturational state of dendritic cells can be modulated by 1,25(OH)2D3, making it possible that the vitamin D status of an individual is likely to have important immunologic consequences.
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3. Vitamin D and autoimmune diseases
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There are several animal models of autoimmunity, in which disease could either be prevented or ameliorated with the administration of either 1,25(OH)2D3 or one of its analogues. These animal models are models of autoimmune encephalomyelitis, collagen-induced arthritis, type 1 diabetes mellitus, inflammatory bowel disease, autoimmune uveitis, and lupus [44, 56, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76]. These studies show that treatment with active vitamin D is effective in modulating immune function and ameliorating autoimmune disease. Vitamin D deficiency is a risk factor for the development of some autoimmune diseases, such as rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), diabetes mellitus type 1, multiples sclerosis, inflammatory bowel disease, and Hashimoto’s thyroiditis [49, 69, 74, 77, 78, 79, 80, 81, 82, 83, 84, 85] (Figure 2). Additionally, vitamin D deficiency has been observed in patients with systemic sclerosis [86].
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Figure 2.
Autoimmune diseases related to vitamin D deficiency.
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3.1 Vitamin D deficiency and rheumatoid arthritis
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A meta-analysis showed that low vitamin D intake is associated with the development of RA [87]. Thereafter, several studies performed in various areas all over the world showed that vitamin D deficiency is observed in patients with RA and that vitamin D deficiency is associated with disease activity [78, 82, 83, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97]. A meta-analysis of the good quality studies performed regarding the association between vitamin D deficiency and RA showed that vitamin D deficiency is observed in RA patients significantly more than in a control group and that vitamin D levels are inversely correlated with disease activity, meaning that low vitamin D levels are associated with high-disease activity [98]. Moreover, an association has been shown between VDR polymorphism and RA. Specifically, the Fokl F allele of the VDR may be a risk factor for the development of RA [99]. Further studies are needed to unravel the exact association between vitamin D deficiency and RA and to determine the best method of vitamin D supplementation and whether it may be used for the prevention of RA or for the best management of the disease [77, 100]. In addition, it has been proposed that vitamin D may contribute to the management of pain in RA and may be used along with TNF-α inhibitors in RA treatment [77, 101].
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3.2 Vitamin D deficiency and systemic lupus erythematosus
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In SLE, the inflammatory milieu drives the development of T cells into proinflammatory pathways, defective function of Tregs, and survival and activation of B cells, which produce autoantibodies [78, 81]. Patients with systemic lupus erythematosus have lower 25(OH)D3 levels compared to controls, suggesting that vitamin D deficiency may be a risk factor for SLE [81, 84, 102, 103, 104, 105, 106, 107]. The majority of studies have also found higher SLE disease activity associated with lower levels of 25(OH)D3 [84, 103]. As patients with SLE have often photosensitivity and are advised to avoid direct sun exposure, detecting vitamin D deficiency and replacing 25(OH)D3 with oral supplementation is critical and may impact disease activity [108].
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3.3 Vitamin D deficiency and type 1 diabetes mellitus
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Type 1 diabetes mellitus is one of the most prevalent chronic diseases with onset in childhood and is the result of immune-mediated destruction of pancreatic insulin producing β cells. There appears to be a geographic variation in incidence following a gradient in latitude, which is the inverse of the global distribution of ultraviolet B irradiation, critical for the production of vitamin D within the skin [109]. Studies have shown higher incidence of vitamin D deficiency in patients with type 1 diabetes [110, 111, 112, 113]. One environmental factor thought to be protective against the development of type 1 diabetes mellitus is early supplementation with vitamin D [114]. A number of large case control studies showed that the risk of type 1 diabetes mellitus was significantly reduced in infants who were supplemented with vitamin D compared to those who were not supplemented [115, 116, 117]. Additionally, a lower incidence of type 1 diabetes was observed in infants born to mothers who were administered cod liver oil during pregnancy [118]. A birth cohort study in Finland, now more than 50 years ago, evaluated the effects of vitamin D supplementation on rickets and the development of type 1 diabetes mellitus [85]. All women due to give birth in 1966 were enrolled. There was an 80% reduction in the risk for type 1 diabetes mellitus in children having received >2000 IU vitamin D/day compared to those receiving less or not receiving supplementation with vitamin D. Evidence from both human and animal studies shows that vitamin D may be protective as far as the development of type 1 diabetes mellitus is concerned [68, 71, 76]. Thus, the administration of vitamin D may prevent diabetes mellitus type 1; however, once the destruction of pancreatic beta cells has taken place, it will not act therapeutically to reverse diabetes mellitus type 1.
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3.4 Vitamin D deficiency and multiple sclerosis
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Multiple sclerosis is characterized by inflammation, demyelination, axonal or neuronal loss, and astrocytic gliosis in the central nervous system, which can result in disability. Epidemiological studies have suggested that vitamin D insufficiency may contribute to the risk of multiple sclerosis [62, 63, 75, 119, 120]. Moreover, several genetic studies in multiple sclerosis patients have shown that diverse abnormalities in vitamin D metabolism are related to the risk of the disease. It appears that vitamin D deficiency may interact with genetic and environmental protective and risk factors, such as the allele HLA BRB1*1501, infections, obesity, smoking, and sexual hormones and may modulate the risk of the disease [63, 74, 80]. Thus, vitamin D deficiency may be a risk modulating factor for the development of multiple sclerosis. Vitamin D acts as an immunomodulatory factor affecting T and B lymphocytes, and it may exert neuroprotector and neurotrophic actions within the central nervous system. Several studies have shown that vitamin D supplementation exerts multiple beneficial immunomodulatory effects in multiple sclerosis [121, 122, 123, 124]. On the contrary, a Cochrane review states that there appears to be no benefit from vitamin D supplementation in patients with multiple sclerosis; however, the level of evidence is very low [125]. Nevertheless, it should be noted that robust statistical models used in association studies have already predicted a favorable vitamin D effect reducing relapses by 50–70% [121]. There is little doubt that vitamin D exerts a beneficial action on multiple sclerosis, the inflammatory component in particular, less so the degenerative. Until more information becomes available, vitamin D supplementation of multiple sclerosis patients, using a moderate physiological dose essentially correcting their vitamin insufficiency, is recommended.
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3.5 Vitamin D and inflammatory bowel disease
\n
Vitamin D deficiency has been observed in patients with inflammatory bowel disease, Crohn’s disease, and ulcerative colitis [126]. It was found to be related to disease activity in Crohn’s disease and ulcerative colitis. Vitamin D supports the integrity of the intestinal barrier and is related to microbiota homeostasis in this cohort of patients [127, 128]. Thus, vitamin D may contribute to the prevention of inflammatory bowel disease by supporting the integrity of the intestinal barrier, contributing to bacterial homeostasis and ameliorating disease progression via anti-inflammatory action. Vitamin D deficiency in inflammatory bowel disease is aggravated by decreased absorption of the vitamin via the gastrointestinal tract [128].
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3.6 Vitamin D deficiency and autoimmune Hashimoto’s thyroiditis
\n
Studies have observed an association between autoimmune Hashimoto’s thyroiditis and low vitamin D levels [79, 129]. These studies have not observed low vitamin D levels in patients with Graves’ disease. A meta-analysis of 26 observational studies confirmed an association between vitamin D deficiency and autoimmune Hashimoto’s thyroiditis [130]. The aforementioned meta-analysis found that although there was heterogeneity between the results of the various studies performed all over the globe, studies had similar results in populations from different countries and also in populations in different age ranges, in particular pediatric and adult populations.
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3.7 Vitamin D deficiency and systemic sclerosis
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Systemic sclerosis is a chronic, inflammatory, fibrotic disorder thought to be related to autoimmune etiology. Vitamin D deficiency has been observed in patients with systemic sclerosis [86, 131], especially in patients with the diffuse type of the disease [131].
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4. Optimal levels of 25(OH)D3
\n
The molecule used to assess vitamin D sufficiency in a population is 25(OH)D3 [9]. It appears that vitamin D has physiologic effects beyond those related to bone physiology and mineral homeostasis. It may be that the alarming prevalence of vitamin D deficiency observed all over the globe may be contributing to the development of autoimmune diseases. Based on bone-related biomarkers such as intact parathyroid hormone, calcium absorption, and bone mineral density, maintaining a 25(OH)D3 level of at least 32 ng/ml appears sufficient.
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5. Conclusions
\n
It appears that vitamin D is a potent immunomodulator. It has multiple and diverse effects on the immune system. In particular, it potentiates the innate immune response enhancing the production of cathelicidin from human macrophages, monocytes, and keratinocytes, thus enhancing and potentiating the immune response against external pathogens. It affects the adaptive immune response shifting the phenotype of the adaptive immune response toward a more tolerogenic phenotype. Vitamin D deficiency is related to various autoimmune disorders. Vitamin D deficiency appears to be related to the development of RA and correlates with disease severity. Vitamin D deficiency is observed in patients with SLE. It was found to be related to disease severity and activity in some but not all studies. Vitamin D deficiency is observed in patients with multiple sclerosis, and vitamin D administration may ameliorate disease severity. Vitamin D deficiency is also observed in patients with inflammatory bowel disease, Crohn’s disease, and ulcerative colitis, and it is related to disease activity. Vitamin D contributes to the integrity of the intestinal barrier and bacterial homeostasis. In addition, vitamin D absorption is decreased making supplementation important. Vitamin D deficiency is also observed in patients with autoimmune Hashimoto’s thyroiditis. Vitamin D deficiency is found in patients with systemic sclerosis, especially the diffuse form of the disease. It appears that optimal levels of vitamin D are important for immune function and for the prevention of autoimmunity in the human organism.
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Conflict of interest
The authors declare no conflict of interest.
\n',keywords:"vitamin D, autoimmunity, rheumatoid arthritis, systemic lupus erythematosus, multiple sclerosis, inflammatory bowel disease, autoimmune Hashimoto’s thyroiditis",chapterPDFUrl:"https://cdn.intechopen.com/pdfs/69633.pdf",chapterXML:"https://mts.intechopen.com/source/xml/69633.xml",downloadPdfUrl:"/chapter/pdf-download/69633",previewPdfUrl:"/chapter/pdf-preview/69633",totalDownloads:1248,totalViews:0,totalCrossrefCites:2,dateSubmitted:"June 6th 2019",dateReviewed:"September 13th 2019",datePrePublished:"October 25th 2019",datePublished:"February 26th 2020",dateFinished:"October 18th 2019",readingETA:"0",abstract:"Vitamin D has many and profound effects on the immune system. Vitamin D deficiency is known to be related to the development of autoimmune diseases. In particular, vitamin D deficiency is related to the development and the severity of rheumatoid arthritis (RA). RA develops in patients with vitamin D deficiency, and the activity of the disease is related to vitamin D deficiency. Vitamin D deficiency is also related to the development of systemic lupus erythematosus (SLE). SLE develops in patients with vitamin D deficiency, and the activity of the disease is also greater in patients with vitamin D deficiency. Vitamin D deficiency is also related to the development and the severity of multiple sclerosis. Vitamin D should be administered to patients with multiple sclerosis, and this seems to mitigate the symptoms of the disease and to prevent disease progression. Vitamin D deficiency is also observed in patients with inflammatory bowel disease and may be related to disease severity. Low vitamin D levels have also been observed in patients with autoimmune Hashimoto’s thyroiditis. Low vitamin D levels have been observed in patients with systemic sclerosis, especially in the diffuse form of the disease. Optimal vitamin D levels appear to be required for normal immune function and for the prevention and treatment of autoimmune diseases.",reviewType:"peer-reviewed",bibtexUrl:"/chapter/bibtex/69633",risUrl:"/chapter/ris/69633",signatures:"Ifigenia Kostoglou-Athanassiou, Lambros Athanassiou and Panagiotis Athanassiou",book:{id:"7038",type:"book",title:"Vitamin D Deficiency",subtitle:null,fullTitle:"Vitamin D Deficiency",slug:"vitamin-d-deficiency",publishedDate:"February 26th 2020",bookSignature:"Julia Fedotova",coverURL:"https://cdn.intechopen.com/books/images_new/7038.jpg",licenceType:"CC BY 3.0",editedByType:"Edited by",isbn:"978-1-83880-776-4",printIsbn:"978-1-83880-775-7",pdfIsbn:"978-1-83880-777-1",isAvailableForWebshopOrdering:!0,editors:[{id:"269070",title:"Prof.",name:"Julia",middleName:null,surname:"Fedotova",slug:"julia-fedotova",fullName:"Julia Fedotova"}],productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"}},authors:null,sections:[{id:"sec_1",title:"1. Introduction",level:"1"},{id:"sec_2",title:"2. Vitamin D and the immune system",level:"1"},{id:"sec_2_2",title:"2.1 Vitamin D and the innate immune system",level:"2"},{id:"sec_3_2",title:"2.2 Vitamin D and autoimmunity",level:"2"},{id:"sec_5",title:"3. Vitamin D and autoimmune diseases",level:"1"},{id:"sec_5_2",title:"3.1 Vitamin D deficiency and rheumatoid arthritis",level:"2"},{id:"sec_6_2",title:"3.2 Vitamin D deficiency and systemic lupus erythematosus",level:"2"},{id:"sec_7_2",title:"3.3 Vitamin D deficiency and type 1 diabetes mellitus",level:"2"},{id:"sec_8_2",title:"3.4 Vitamin D deficiency and multiple sclerosis",level:"2"},{id:"sec_9_2",title:"3.5 Vitamin D and inflammatory bowel disease",level:"2"},{id:"sec_10_2",title:"3.6 Vitamin D deficiency and autoimmune Hashimoto’s thyroiditis",level:"2"},{id:"sec_11_2",title:"3.7 Vitamin D deficiency and systemic sclerosis",level:"2"},{id:"sec_13",title:"4. Optimal levels of 25(OH)D3",level:"1"},{id:"sec_14",title:"5. 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Analogs of 1alpha,25-dihydroxyvitamin D3 as pluripotent immunomodulators. Journal of Cellular Biochemistry. 2003;88(2):223-226. DOI: 10.1002/jcb.10329\n'},{id:"B66",body:'Cantorna MT, Hayes CE, DeLuca HF. 1,25-dihydroxycholecalciferol inhibits the progression of arthritis in murine models of human arthritis. The Journal of Nutrition. 1998;128(1):68-72. DOI: 10.1093/jn/128.1.68\n'},{id:"B67",body:'Larsson P, Mattsson L, Klareskog L, Johnsson C. A vitamin D analogue (MC 1288) has immunomodulatory properties and suppresses collagen-induced arthritis (CIA) without causing hypercalcaemia. Clinical and Experimental Immunology. 1998;114(2):277-283. DOI: 10.1046/j.1365-2249.1998.00706.x\n'},{id:"B68",body:'Zella JB, McCary LC, DeLuca HF. Oral administration of 1,25-dihydroxyvitamin D3 completely protects NOD mice from insulin-dependent diabetes mellitus. 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Australian children and adolescents with type 1 diabetes have low vitamin D levels. The Medical Journal of Australia. 2007;187:59-60\n'},{id:"B113",body:'Daga RA, Laway BA, Shah ZA, Mir SA, Kotwal SK, Zargar AH. High prevalence of vitamin D deficiency among newly diagnosed youth-onset diabetes mellitus in North India. Arquivos Brasileiros de Endocrinologia e Metabologia. 2012;56(7):423-428\n'},{id:"B114",body:'Zella JB, DeLuca HF. Vitamin D and autoimmune diabetes. Journal of Cellular Biochemistry. 2003;88(2):216-222\n'},{id:"B115",body:'Dong JY, Zhang WG, Chen JJ, Zhang ZL, Han SF, Qin LQ. Vitamin D intake and risk of type 1 diabetes: A meta-analysis of observational studies. Nutrients. 2013;5(9):3551-3562\n'},{id:"B116",body:'Zipitis CS, Akobeng AK. Vitamin D supplementation in early childhood and risk of type 1 diabetes: A systematic review and meta-analysis. Archives of Disease in Childhood. 2008;93(6):512-517\n'},{id:"B117",body:'Stene LC, Joner G. 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\r\n\tIf we aim to prosper as a society and as a species, there is no alternative to sustainability-oriented development and growth. Sustainable development is no longer a choice but a necessity for us all. Ecosystems and preserving ecosystem services and inclusive urban development present promising solutions to environmental problems. Contextually, the emphasis on studying these fields will enable us to identify and define the critical factors for territorial success in the upcoming decades to be considered by the main-actors, decision and policy makers, technicians, and public in general.
\r\n
\r\n\tHolistic urban planning and environmental management are therefore crucial spheres that will define sustainable trajectories for our urbanizing planet. This urban and environmental planning topic aims to attract contributions that address sustainable urban development challenges and solutions, including integrated urban water management, planning for the urban circular economy, monitoring of risks, contingency planning and response to disasters, among several other challenges and solutions.
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